IL-1 signaling modulates STAT activation to antagonize retinoic acid signaling and control Th17–iTreg balance

Interleukin 17 (IL-17)-producing helper (T(H)17) and inducible regulatory CD4(+) T (iT(reg)) cells emerge from an overlapping developmental program. In the intestines, the vitamin A metabolite retinoic acid (RA) is produced at steady state and acts as an important cofactor to induce iT(reg) cell development while potently inhibiting T(H)17 development. Here, we found that IL-1 was required to fully override RA-mediated Foxp3 expression and induce protective T(H)17 responses. Through induction of an NF-κB-dependent repression of SOCS3 expression, IL-1 increased the amplitude and duration of STAT3 phosphorylation induced by T(H)17-polarizing cytokines, leading to an altered balance of STAT3–STAT5 binding to shared consensus sequences in developing T cells. Thus, IL-1 signaling differentially modulated STAT activation downstream of cytokine receptors to control T(H)17–iT(reg) developmental fate.